Process for deuteration of inert methylene

ABSTRACT

The present invention relates to a method for deuteration of an inert alkane using activated palladium carbon. The present invention discloses “A method for deuteration of a hydrogen atom of a methyl group or a hydrogen atom bonded to a carbon atom at benzyl position and the other carbon atoms of an alkylene group having not less than 2 carbon atoms, in a compound containing the methyl group or the-alkylene group having not less than 2 carbon atoms, directly bonded to an aromatic ring which may have a substituent, which comprises placing said compound in a deuterated solvent in the presence of activated palladium carbon, under sealed reflux condition”.

TECHNICAL FIELD

The present invention relates to a method for deuteration of an inertalkane using activated palladium carbon.

BACKGROUND OF THE INVENTION

A compound labeled with an isotope is useful to examine in vivo kineticsof drug, in particular, a compound labeled with deuterium (D) isgenerally utilized for this purpose.

The compound labeled with deuterium has generally been synthesized by aconventional method using a preliminary deuterated starting material,however, said synthetic method has a problem with requiring multiplesynthetic steps, so it is desired to develop a method for obtaining acompound labeled with deuterium by directly exchanging C—H of a finalobjective compound for C-D (H-D exchange).

The present inventors have conducted extensive study and have found amethod for selective deuteration of only a hydrogen atom binded to acarbon atom directly bonded to an aromatic ring (a hydrogen atom at thebenzyl position). However, said deuteration method provides still lowdeuteration rate of a hydrogen atom at terminal carbon even at benzylposition (a hydrogen atom of a methyl group directly bonded to anaromatic ring) and no deuteration of a hydrogen atom bonded to-a carbonatom other than at benzyl position. Therefore, it has been desired todevelop a method for attaining high deuteration rate of a hydrogen atomof a methyl group directly bonded to an aromatic ring and alsodeuteration of a hydrogen atom bonded to a carbon atom other than atbenzyl position.

Therefore, the purpose of the present invention is to develop a methodfor high deuteration rate of a hydrogen atom in a methyl group directlybonded to an aromatic ring and also an effective deuteration of not onlya hydrogen atom at benzyl position but also a hydrogen atom bonded tothe other carbon atoms.

SUMMARY OF THE INVENTION

The present inventors have studied extensively to solve theabove-described problem and found that the reaction of a compound havinga methyl group or an alkylene group, directly bonded to an aromatic ringwhich may have a substituent, and a deuterated solvent in the presenceof an activated palladium carbon catalyst under sealed reflux conditioncan deuterate not only a hydrogen atom of said methyl group and saidcarbon atom bonded to at benzyl position, in said compound, but also ahydrogen atom bonded to a carbon atom other than at benzyl position insaid compound, and finally the present invention has been completed onthe basis of these findings. The present invention relates to;

A method for deuteration of a hydrogen atom of a methyl group or ahydrogen atom bonded to a carbon atom at benzyl position and the othercarbon atoms of an alkylene group having not less than 2 carbon atoms,in a compound containing the methyl group or the alkylene group havingnot less than 2 carbon atoms, directly bonded to an aromatic ring whichmay have a substituent, which comprises placing said compound in adeuterated solvent in the presence of activated palladium carbon, undersealed reflux condition.

BEST MODE FOR CARRYING OUT THE INVENTION

In the compound containing a methyl group or an alkylene group havingnot less than 2 carbon atoms, directly bonded to an aromatic ring whichmay have a substituent, of the present invention, the compoundcontaining a methyl group or an alkylene group having not less than 2carbon atoms, directly bonded to an aromatic ring, includes for example,a compound represented by the general formula [1]:

(wherein A is a methylene group or an alkylene group having not lessthan 2 carbon atoms; X is a hydrogen atom, an alkoxy group, a carboxylgroup, a hydroxyl group, an amino group, an acyl group, an acylaminogroup or an alkoxycarbonyl group; and when A is a methylene group, X isa hydrogen atom.) In the general formula [1], the alkylene group havingnot less than 2 carbon atoms, represented by A, may be straight chained,branched or cyclic, preferably straight chained or branched and morepreferably straight chained, and includes one having generally 2 to 20,preferably 2 to 10 and more preferably 2 to 7 carbon atoms.

The specific example of the alkylene group having not less than 2 carbonatoms, represented by A, includes such as an ethylene group, amethylmethylene group, a n-propylene group, an isopropylene group, an-butylene group, an isobutylene group, a 1,2-dimethylethylene group, an-pentylene group, an isopentylene group, a 2-methylbutylene group, a1,2-dimethylpropylene group, a n-hexylene group, an isohexylene group, a2-methylpentylene group, a 1,4-dimethylbutylene group, a2,3-dimethylbutylene group, a n-heptylene group, an isoheptylene group,a 1,2-dimethylpentylene group, a 1,2,3-trimethylbutylene group, ann-octylene group, a n-nonylene group, a n-decylene group, ann-undecylene group, a n-dodecylene group, a n-tridecylene group, an-tetradecylene group, a n-pentadecylene group, a n-hexadecylene-group,a n-heptadecylene group, an n-octadecylene group, a n-nonadecylenegroup, an n-icosylene group, a cyclopentylene group, a cyclohexylenegroup, a cycloheptylene group, a cyclooctylene group, a cyclononylenegroup, a cyclodecylene group, a cycloundecylene group, a cyclododecylenegroup, a cyclotridecylene group, a cyclotetradecylene group, acyclohexadecylene group, a cycloheptadecylene group, a cyclononadecylenegroup and a cycloicosylene group. Among others, the above-describedalkylene group having not less than 5 carbon atoms may be substitutedwith an oxygen atom at fourth or more carbon atom from the carbon atomdirectly bonded to the aromatic ring thereof.

In the general formula [1], the alkoxy group represented by X includesone having generally 1 to 6 carbon atoms, preferably 1 to 4 carbonatoms, which is specifically exemplified by such as a methoxy group, anethoxy group, a propoxy group, a butoxy group, a pentyloxy group and ahexyloxy group.

The carboxyl group represented by X may be a salt of an alkali metalsuch as sodium, potassium and lithium, and a salt of an alkaline earthmetal such as calcium and magnesium, and among others, preferably analkali metal salt because of easy handling, and more preferably a sodiumsalt.

The amino group represented by X includes a primary amino group (—NH₂),a secondary amino group (—NHR) and a tertiary amino group (—NR₂)(wherein R is an alkyl group having 1 to 6, preferably 1 to 4 carbonatoms) which is specifically exemplified by a primary amino group; asecondary amino group such as a methylamino group, an ethylamino group,a propylamino group, a butylamino group, a pentylamino group and ahexylamino group; and a tertiary amino group such as a dimethylaminogroup, a diethylamino group, a dipropylamino group, a dibutylaminogroup, a dipentylamino group and a dihexylamino group, and among others,a primary amino group is preferable.

The acyl group represented by X includes one derived from an aliphaticcarboxylic acid having generally 2 to 10 carbon atoms such as an acetylgroup, a propionyl group, a butyryl group, an isobutyryl group, avaleryl group, an isovaleryl group and a pivaloyl group; and one derivedfrom an aromatic carboxylic acid such as a benzoyl group.

The acylamino group represented by X includes a group wherein —NH— bondis bonded further to the carbonyl group of the above acyl group, whichis specifically exemplified by an acetylamino group, a propionylaminogroup, a butyrylamino group, an isobutyrylamino group, a valerylaminogroup, an isovalerylamino group, a pivaloylamino group and abenzoylamino group.

The alkoxycarbonyl group represented by X includes one having generally2 to 7 carbon atoms, which is specifically exemplified by such as amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,a pentyloxycarbonyl group and a hexyloxycarbonyl group.

Further, when X is an alkoxy group, a hydroxyl group or an amino group,A is preferably a straight-chained alkylene group having not less than 3carbon atoms.

Among the hydrogen atoms bonded to the aromatic ring in the compoundrepresented by the general formula [1], generally 1 to 5, preferably 1to 2, more preferably 1 hydrogen atom may be substituted eachindependently with such as an alkyl group, an aryl group, an aralkylgroup, an alkoxy group, a nitro group and an amino group.

Further, the alkyl group when a hydrogen atom of an aromatic ring issubstituted with an alkyl group may be straight chained or branched,preferably straight chained, and includes one having generally 1 to 10carbon atoms, preferably 1 to 6 carbon atoms, which is specificallyexemplified by a methyl group, an ethyl group, a n-propyl group, anisopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group,a tert-butyl group, a n-pentyl group, an isopentyl group, a sec-pentylgroup, a tert-pentyl -group, a neopentyl group, a n-hexyl group, anisohexyl group, a 2,2-dimethylbutyl group, a n-heptyl group, anisoheptyl group, a sec-heptyl group, a tert-heptyl group, an n-octylgroup, an isooctyl group, a n-nonyl group, an isononyl group, asec-nonyl group and a n-decyl group.

The aryl group when a hydrogen atom of an aromatic ring is substitutedwith an aryl group includes one having generally 6 to 14 carbon atoms,which is specifically exemplified by a phenyl group, a naphthyl groupand an anthryl group.

The aralkyl group when a hydrogen atom of an aromatic ring issubstituted with an aralkyl group includes one having generally 7 to 10carbon atoms, which is specifically exemplified by such as a benzylgroup, a phenylethyl group, a phenylpropyl group and a phenylbutylgroup.

The alkoxy group when a hydrogen atom of an aromatic ring is substitutedwith an alkoxy group may be straight chained or branched, and includesone having generally 1 to 6 carbon atoms, preferably 1 to 4 carbonatoms, which is specifically exemplified by such as a methoxy group, anethoxy group, a propoxy group, a butoxy group, a pentyloxy group and ahexyloxy group.

The amino group when a hydrogen atom of an aromatic ring is substitutedwith an amino group may be the same as examples of the amino grouprepresented by X in the general formula [1] described above.

Among the compounds represented by the general formula [1], one havingno substituent in the aromatic ring thereof is preferable.

The specific example of the compound represented by the above-describedgeneral formula [1] includes a compound having a methyl group directlybonded to the aromatic ring such as:

and a compound containing an alkylene group having not less than 2carbon atoms directly bonded to the aromatic ring such as:

In the method for deuteration of the present invention, the activatedpalladium carbon used as a catalyst is such so-called “palladium carbon”as activated by contact with hydrogen gas.

In the method for deuteration of the present invention, as the activatedpalladium carbon, a palladium carbon preliminarily activated by forexample, hydrogen gas may be used, or a non-activated palladium carboncan also be used if hydrogen gas is present in a deuteration reactionsystem.

An amount of the non-activated palladium carbon or activated palladiumcarbon to be used is generally 0.1 to 50% by weight, preferably 3 to 10%by weight, relative to the amount of the compound containing a methylgroup or an alkylene group having not less than 2 carbon atoms directlybonded to the aromatic ring which may have a substituent, used asreaction substrate.

Further, in the case of using non-activated palladium carbon for thereaction of the present invention, use of too much hydrogen gas in thereaction system causes hydrogenation of a deuterated solvent and thusaffects deuteration reaction itself of the present invention. Therefore,an appropriate amount of hydrogen gas is such quantity as necessary toactivate palladium carbon, and an amount of hydrogen gas to be used isgenerally 1 to 20000, preferably 10 to 700 equivalents weight, relativeto the amount of palladium in palladium carbon.

The specific example of a deuterated solvent to be used in the methodfor deuteration of the present invention includes deuterium oxide;deuterated alcohols such as deuterated methanol, deuterated ethanol,deuterated isopropanol, deuterated butanol, deuterated tert-butanol,deuterated pentanol, deuterated hexanol, deuterated heptanol, deuteratedoctanol, deuterated nonanol, deuterated decanol, deuterated undecanoland deuterated dodecanol; deuterated carboxylic acids such as deuteratedformic acid, deuterated acetic acid, deuterated propionic acid,deuterated-butyric-acid, deuterated isobutyric acid, deuterated valericacid, deuterated isovaleric acid and deuterated pivalic acids;deuterated ketones such as deuterated acetone, deuterated methyl ethylketone, deuterated methyl isobutyl ketone, deuterated diethyl ketone,deuterated dipropyl ketone, deuterated diisopropyl ketone and deuterateddibutyl ketone; and deuterated dimethylsulfoxide, and among others,deuterium oxide and deuterated methanol are preferable. These solventsmay be ones deuterating at least one hydrogen atom in a molecularthereof, and specifically deuterated alcohols, wherein a hydrogen atomof a hydroxyl group is deuterated, or deuterated carboxylic acids,wherein a hydrogen atom of a carboxyl group is deuterated, can be usedin the method for deuteration of the present invention. Among others, asolvent wherein all hydrogen atoms of a molecule thereof are deuteratedis more preferable.

An amount of the deuterated solvent to be used is the amount so thatgenerally 1 to 1000 equivalent weights, preferably 10 to 250 equivalentweights of deuterium atom is contained in said solvent, relative to thecompound containing a methyl group or an alkylene group having not lessthan 2 carbon atoms directly bonded to an aromatic ring which may have asubstituent, used as reaction substrate, if theoretical quantity of adeuterium atom required to replace a hydrogen atom at an exchangeposition is 1 equivalent weight.

A reaction temperature in the method for deuteration of the presentinvention may be set at generally not lower than boiling temperature(under normal pressure) of the solvent to retain refluxing state,preferably boiling temperature to boiling temperature +30° C., morepreferably boiling temperature to boiling temperature +20° C. andfurther more preferably boiling temperature +5° C. to boilingtemperature +15° C.

A sealed reaction system may be heated and/or pressurized to setreaction temperature described above, and-consequently attainpressurized state.

An inert gas such as nitrogen gas and argon gas may be used topressurize a reaction system.

A reaction time is generally 1 to 100 hours, preferably 10 to 50 hoursand more preferably 15 to 30 hours.

The method for deuteration of the present invention is concretelyexplained taking the case of using deuterium oxide as a solvent.

Namely, for example, in 1 ml of deuterium oxide are suspended 0.25 mmolof the compound (substrate) represented by the general formula [1] andabout 10% by weight of non-activated palladium carbon (Pd 10%) relativeto the amount of said substrate. Then, the atmosphere of the sealedreaction system is replaced with hydrogen gas, followed by reacting byheating under reflux for about 24 hours in an oil-bath. After completionof the reaction, the reaction solution is filtered to be subjected as itis to structural analysis by ¹H-NMR and mass spectrometry measurement,when the reaction product is soluble in deuterium oxide. When thereaction product is hardly soluble in deuterium oxide, the reactionproduct is isolated from the reaction solution to be subjected tostructural analysis of the reaction product by ¹H-NMR and massspectrometry measurement.

The isolation of the products from the reaction solution in the case ofthe products hardly soluble in deuterium oxide may be carried outaccording to a known purification method.

In a compound represented by the general formula [1], it is estimatedthat the deuteration of an -A-X group or a substituent of an aromaticring can obtain high deuteration rate of a hydrogen atom bonded to acarbon atom closer to the aromatic ring.

Further, in the case that an oxygen atom is included in a grouprepresented by an -A-X group or in an alkyl chain bonded to an aromaticring as a substituent, it is difficult to deuterate a hydrogen atombonded to a carbon atom next to said oxygen atom and a carbon atomlocated far from said oxygen atom viewed from the aromatic ring.

When the compound having a substituent such as a nitro group, among thecompounds represented by the general formula [1], is used as a reactionsubstrate and hydrogen gas is used to activate a catalyst in a reactionsystem for deuteration reaction, a substituent such as nitro group ofsaid substrate may be reduced to an amino group and the like in additionto deuteration of the present invention.

As mentioned above, a hydrogen atom of a methyl group directly bonded toan aromatic ring, which could be deuterated but at a low ratio by aconventional method, can be deuterated very effectively and also notonly a hydrogen atom at a benzyl position in an alkylene group havingnot less than 2 carbon atoms but also a hydrogen atom other than at abenzyl position, which could not be deuterated by a conventional method,can be deuterated by a deuteration method of the present invention,characterized by reaction of substrate using an activated palladiumcarbon and a deuterated solvent under sealed reflux condition.

In the following, the present invention is explained in further detailreferring to examples, but the present invention is not limited theretoby any means.

EXAMPLE Example 1

In 1 ml of deuterium oxide were suspended 0.25 mmol of a compoundrepresented by the above mentioned formula, 10% by weight of palladiumcarbon (Pd 10%) relative to said compound, and 0.25 mmol of p-anisicacid as an internal standard, followed by replacing the atmosphere of areaction system with hydrogen gas using a balloon and contacting thereaction solution with hydrogen gas. The reaction solution was heated at110° C. for 24 hours in an oil-bath, followed by filtering with amembrane filter. The filtrate was subject as it is to structuralanalysis of products by ¹H-NMR and mass spectrometry measurement. Theresult showed that a hydrogen atom of the aromatic ring and a hydrogenatom of the alkylene group bonded to the aromatic ring, in raw materialwere deuterated. Deuteration rate (%) of each hydrogen atom bonded to acarbon atom in the compound is shown in Table 1. TABLE 1 Reactiontemperature Ph C1 C2 + C3 C4 Example 1 110° C. 21 93 88 53 ComparativeRoom temperature 0 89 0 0 Example 1

In the Table, “Ph” means a carbon atom in an aromatic ring, “C1”,“C2+C3” and “C4” mean a carbon atom denoted by the number in thefollowing formula, respectively. The numbers in the Table showdeuteration rate of the hydrogen atom bonded to each carbon atom.

Comparative Example 1

Deuteration was carried out by the same procedure as in Example 1,except for carrying out the reaction at room temperature. Deuterationrate (%) of the hydrogen atom bonded to the carbon atom in the compoundis shown in Table 1.

Comparative Examples 2 and 3

Deuteration was carried out by the same procedure as in Example 1 usingsubstrate compounds without an aromatic ring, shown by the followingformula, but deuteration of both compounds did not occur at all.

Examples 2 to 8

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown in Table 2 as substrates.Deuteration rate (%) of the hydrogen atom bonded to the carbon atom inthe compound is shown in Table 2. TABLE 2 Use Amount substrate (mmol) PhC1 C2 C3 C4 C5 C6 C7 Exam. 2 PhCH₃ 5 0 64 — — — — — — Exam. 3 PhCH₂CH₃ 40 59 52 — — — — — Exam. 4 Ph(CH₂)₂CH₃ 4 19 77 75 56 — — — — Exam. 5Ph(CH₂)₃CH₃ 3 51 74 75 72 70 — — — Exam. 6 Ph(CH₂)₄CH₃ 0.25 0 85 80 12 0— — Exam. 7 Ph(CH₂)₅CH₃ 0.25 32 90 96 36 11 — Exam. 8 Ph(CH₂)₆CH₃ 0.2520 93 59 17 10

In the Table, “-” represents no presence of a relevant hydrogen atom;“Ph” means a carbon atom in an aromatic ring; and “C1 to C7” representthe carbon atom numbered in the order from a carbon atom close bonded toan aromatic ring. The numbers in the Table show deuteration rate of thehydrogen atom bonded to each carbon atom (the same hereinafter).

Examples 9 to 12

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown in Table 3 as substrates.Deuteration rate (%) of the hydrogen atom bonded to the carbon atom inthe compound is shown in Table 3. TABLE 3 Substrate Ph C1 C2 C3 C4 C5Terminal H Example 9 Ph(CH₂)₂COOH 0 91 77 — — — 100 Example Ph(CH₂)₃COOH33 96 97 55 — — 100 10 Example Ph(CH₂)₄COOH 26 97 80 0 — 100 11 ExamplePh(CH₂)₅COOH 21 94 (A) 81 (B) 0 100 12* (A) + (B) = 60%

In the Table, “terminal H” means a hydrogen atom in a carboxyl group.The numbers in the Table show deuteration rate thereof.

Example 13

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown in Table 4 as substrates.Deuteration rate (%) of the hydrogen atom bonded to the carbon atom inthe compound is shown in Table 4. TABLE 4 Substrate Ph C1 C2 + C3 C4 C5Example 13 Ph(CH₂)₄COOCH₃ 0 90 91 0 0

In the Table, “Ph”, “C1”, “C2”, “C3”, “C4” and “C5” represent the carbonatoms denoted by the number in the following formula, respectively.

Examples 14 to 16

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown in Table 5 as substrates.Deuteration rate (%) of the hydrogen atom bonded to the carbon atom inthe compound is shown in Table 5. TABLE 5 Substrate Ph C1 C2 C3 C4 C5Example 14 Ph(CH₂)₃OH 0 92 31 0 — — Example 15 Ph(CH₂)₄OH 0 90 24 32 0 —Example 16 Ph(CH₂)₅OH 0 89 (A) 39 (B) 0* (A) + (B) = 42%

Examples 17 and 18

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown by the following formula assubstrates. Deuteration rate (%) of the hydrogen atom bonded to thecarbon atom in the compound is shown in Table 6. TABLE 6

Substrate Ph Cl C2 C3 C4 C5 Example 17 Ph(CH₂)₃OCH₃ 0 91 88 0 0 —Example 18 Ph(CH₂)₃OCH₂CH₃ 0 96 99 0 0 0

Comparative Examples 4 and 5

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown by the following for mula assubstrates, however, deuteration of any compound did not occur at all.

Examples 19 to 24

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown the following formula as substratesin the amount shown in the Table below. Deuteration rate (%) of thehydrogen atom bonded to the carbon atom in the compound is shown inTable 7. X represents a substituent shown in Table 7. TABLE 8

Amount of Deuteration Substrate Product substrate rate Exam. 25

5 mmol 64% Exam. 26

0.25 mmol 94% Exam. 27

0.25 mmol 92% Exam. 28

3 mmol 81% Exam. 29

0.25 mmol 95% *deuteration on rate of an aromatic ring: 56% Exam. 30

0.25 mmol 92% *deuteration on rate of an aromatic ring: 63%

Examples 25 to 30

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown in Table 8 as substrates in theamount in the following table. Deuteration rate (%) of the hydrogen atombonded to the carbon atom in the compound is shown in Table 8.

Examples 31 to 33

Deuteration was carried out by the same procedure as in Example 1,except for using the compounds shown in Table 9 substrates, usingdeuterated methanol as a reaction solvent instead of deuterium oxide,and conducting the reaction at 80° C. Deuteration rate (%) of thehydrogen atom bonded to the carbon atom in the compound is shown inTable 9. TABLE 9 Substrate Ph C1 C2 C3 C4 C5 Example 31 Ph(CH₂)₂CH₃ 0 5926  4 — — Example 32 Ph(CH₂)₃CH₃ 0 73 69 10 0 — Example 33 Ph(CH₂)₄CH₃ 081 70 10 5

Example 34

Deuteration was carried out by the same procedure as in Example 1,except for using ibuprofen represented by the following formula assubstrate. Deuteration rate (%) is shown in Table 10. TABLE 10

C1 C2 C3 C4 Terminal H Example 34 50 96 94 50 100 Comparative 0 1 18 0100 Example 6

Comparative Example 6

Deuteration was carried out by the same procedure as in Example 34,except for carrying out a reaction at room temperature. Deuteration rate(%) is shown in Table 10.

As is clear from comparison of deuteration rates between Example 1 andComparative Example 1 and between Example 34 and Comparative Example 6,although in case of the deuteration reaction at room temperature, ahydrogen atom of a carbon atom only at a benzyl position can bedeuterated slightly, the deuteration reaction under reflux can deuteratea hydrogen atom bonded to not only alkyl carbon at a benzyl position butalso other than at a benzyl position at high rate.

Further, it is clear from the results of Comparative Examples 2 and 3that an aliphatic compound having no aromatic ring cannot be deuterated

Furthermore, as is clear from the results of Examples 2 to 8 and 31 to33, deuteration rate of a hydrogen atom bonded to a carbon atom at farposition from an aromatic ring becomes lower, according as the number ofcarbon atoms of alkyl group directly bonded to an aromatic ringincreases.

It is clear from the results of Examples 2 to 8, 17, 18, 25 to 28 and 31to 33, that even a compound showing low solubility in a deuteratedsolvent can be deuterated by a method for deuteration of the presentinvention.

Further, as is clear from Examples 17 and 18, in the case of an aromaticcompound containing an oxygen atom in the alkyl chain, it is difficultto deuterate a hydrogen atom bonded to a carbon atom next to the oxygenatom and a hydrogen atom of a carbon atom at far position from saidoxygen atom viewed from an aromatic ring.

INDUSTIAL APPLICABILITY

By the method of the present invention, characterized by reaction of acompound containing a methyl group or an alkylene group having not lessthan 2 carbon atoms directly bonded to an aromatic ring which may have asubstituent, and a deuterated solvent in the presence of an activatedpalladium carbon catalyst under sealed reflux condition, a hydrogen atomof said methyl group, which could be deuterated but at low deuterationrate by a conventional method, can be deuterated very effectively, andfurther deuteration of not only a hydrogen atom at a benzyl position inan alkylene group having not less than 2 carbon atoms but also ahydrogen atom other than at a benzyl position, whose deuteration wereimpossible by a conventional method, is now possible.

1. A method for deuteration of a hydrogen atom of a methyl group or ahydrogen atom bonded to a carbon atom at benzyl position and the othercarbon atoms of an alkylene group having not less than 2 carbon atoms,in a compound containing the methyl group or the alkylene group havingnot less than 2 carbon atoms, directly bonded to an aromatic ring whichmay have a substituent, which comprises placing said compound in adeuterated solvent in the presence of activated palladium carbon, undersealed reflux condition.
 2. The method for deuteration according toclaim 1, wherein said compound containing the methyl group or thealkylene group having not less than 2 carbon atoms, directly bonded tothe aromatic ring which may have the substituent is a compound havingsaid methyl group.
 3. The method for deuteration according to claim 1,wherein said compound containing the methyl group or the alkylene grouphaving not less than 2 carbon atoms, directly bonded to the aromaticring which may have the substituent, is a compound containing saidalkylene group having not less than 2 carbon atoms, directly bonded tothe aromatic ring which may have a substituent.
 4. The method fordeuteration according to claim 1, wherein said compound containing themethyl group or the alkylene group having not less than 2 carbon atoms,directly bonded to the aromatic ring, in said compound containing themethyl group or the alkylene group having not less than 2 carbon atoms,directly bonded to the aromatic ring which may have the substituent, isa compound represented by the general formula [1]:

(wherein A is a methylene group or an alkylene group having not lessthan 2 carbon atoms; and X is a hydrogen atom, an alkoxy group, acarboxyl group, a hydroxyl group, an amino group, an acyl group, anacylamino group or an alkoxycarbonyl group; and when A is a methylenegroup, X is a hydrogen atom).
 5. The method for deuteration according toclaim 4, wherein the alkylene group having not less than 2 carbon atoms,represented by A is a straight chained alkylene group and X is ahydrogen atom, a carboxyl group, an acyl group, an acylamino group or analkoxycarbonyl group.
 6. The method for deuteration according to claim4, wherein the alkylene group having not less than 2 carbon atoms,represented by A is a straight chained alkylene group having not lessthan 3 carbon atoms and X is an alkoxy group, a hydroxyl group or anamino group.
 7. The method for deuteration according to claim 1, whereinthe substituent, which an aromatic ring may have, is one selected fromthe group consisting of an alkyl group, an aryl group, an aralkyl group,an alkoxy group, a nitro group and an amino group.
 8. A compoundrepresented by the general formula [2]:

(wherein n is 3, 4 or 5).